OVERVIEW SUMMARY/ABSTRACT Lung cancer is the leading cause of cancer-related deaths, with more than 1.6 million deaths/year globally. It is often diagnosed at an advanced stage and is associated with poor outcomes for the majority of patients. This application for a lung cancer SPORE award from Emory University brings together an outstanding and multi- disciplinary team of oncologists, immunologists, drug discovery experts, and translational researchers dedicated to lung cancer research to address critical questions that will improve the outcome for patients with this lethal disease. Our proposed program will have significant impact in two crucial areas of lung cancer management: enhancing the efficacy of immunotherapy and overcoming treatment resistance through the development of novel molecularly targeted agents. Through strong teamwork carried out by this highly collaborative team of dedicated investigators, and building on exciting data published in leading journals by our group since our previous SPORE application, this revised submission aims to achieve substantial improvements in the management of patients with non-small cell lung cancer (NSCLC), through three overall Specific Aims: Aim 1: To evaluate stem-like T cells and improve efficacy of checkpoint inhibitors in NSCLC (Project 1); Aim 2: To target MERTK to improve outcomes for EGFR-mutated NSCLC (Project 2); and Aim 3: To target Bax signaling to overcome treatment resistance in NSCLC (Project 3). The Emory Lung Cancer SPORE program will be supported by close interaction with the Administrative Core (Core 1), Pathology Core (Core 2) and the Biostatistics and Biomedical Informatics Core (Core 3), and will conduct Career Enhancement and Developmental Research Programs (CEP and DRP). The SPORE program will benefit from regular advice and recommendations from External and Internal Advisory Board members regarding its progress and direction. Our program will receive strong institutional support including modern research space, excellent shared resources, and a significant level of matching funds (totaling $2.25M) from the Winship Cancer Institute of Emory University (an NCI-designated Comprehensive Cancer Center), Emory University Woodruff Health Sciences Center, Emory Healthcare System, Emory School of Medicine, and the Department of Hematology and Medical Oncology. Through team-driven innovative research efforts in immunotherapies and molecularly targeted therapeutics, we are confident that this SPORE program, in collaboration with other lung cancer SPORE sites, will have a major positive impact on the management of lung cancer.